During the past 15 years, cocaine has risen from a drug of minor public concern to its present position as a major drug of abuse. In fact, cocaine abuse has been described as a "national epidemic" with significant attendant health problems. The potent rewarding effect of cocaine, more than anything else, probably accounts for the meteoric rise in abuse prevelance. Animal studies have demonstrated that the dopamine (DA) containing neuronal tracts originating in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc) and medial prefrontal cortex (MPC) are specifically involved in the rewarding properties of cocaine. Surprisingly, there have been no reports regarding the effects of cocaine on the activity of single neurons within these brain areas. The present proposal outlines a research plan designed to identify the effects of cocaine on the electrophysiological properties of several neuronal populations including the A10 DA neurons within the NAc and MPC. These experiments will use single unit recording, microiontophoresis and electrical stimulation techniques as well as in vitro slice recording and DA uptake preparations to identify the specific neuropharmacologic mechanisms by which cocaine alters neuronal activity within these DA pathways. In addition, a series of studies is proposed which will attempt to characterize the interactions between the neuronal effects of cocaine and other drugs such as benzodiazepines and opiates which are commonly used in combination with cocaine. Other experiments will attempt to define the neuronal alterations brought about by long-term cocaine administration which may relate to issues of cocaine tolerance, sensitization, dependence and withdrawal. Finally, studies will be conducted to determine whether antidepressant drugs such as the tricyclics might reverse any observed effects of withdrawal from long-term cocaine use in view of recent reports indicating that such pharmacological treatment may be of benefit in treating cocaine abusers. It is hoped that the results of these experiments will help to define the neurobiological concomitants of cocaine use, particularly as they might relate to reward mechanisms. Furthermore, these studies should provide important information regarding the consequences of long-term cocaine use and potential pharmacologic treatment strategies.